The inhibition of human neutrophil elastase and cathepsin G by peptidyl 1,2-dicarbonyl derivatives.
Neutrophil elastase and cathepsin G are serine proteases that can damage connective tissue and trigger other pathological reactions. Compounds containing a peptide sequence to impart specificity and bearing an alpha-dicarbonyl unit (alpha-diketone or alpha-keto ester) at the carboxy terminus are potent inhibitors of the neutrophil serine proteases (human neutrophil elastase: R-Val-COCH3, Ki = 0.017 microM; R-Val-COOCH3, Ki = 0.002 microM; human neutrophil cathepsin G: R-Phe-COCH3, Ki = 0.8 microM; R-Phe-COOCH3, Ki = 0.44 microM; R = N-(4-[(4-chlorophenyl)sulfonylaminocarbonyl]phenylcarbonyl)+ ++ValylProlyl).
Mehdi
S
S
Merrell Dow Research Institute, Cincinnati, OH 45215.
Angelastro
M R
MR
Burkhart
J P
JP
Koehl
J R
JR
Peet
N P
NP
Bey
P
P
D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors; D056649:Cathepsin G; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D002417:Cattle; D002645:Chickens; D002918:Chymotrypsin / Q000037:antagonists & inhibitors; D006801:Humans; D066298:In Vitro Techniques; D007659:Ketones / Q000494:pharmacology*; D007700:Kinetics; D019272:Leukocyte Elastase; D015260:Neprilysin / Q000037:antagonists & inhibitors; D009504:Neutrophils / Q000201:enzymology*; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D010455:Peptides / Q000494:pharmacology*; D011480:Protease Inhibitors; D051381:Rats; D012697:Serine Endopeptidases; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors
D007659:Ketones; D010455:Peptides; D011480:Protease Inhibitors; D002403:Cathepsins; D012697:Serine Endopeptidases; D002918:Chymotrypsin; C534094:CTSG protein, human; D056649:Cathepsin G; C534097:Ctsg protein, rat; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase; D013917:Thrombin; D002154:Calpain; D015260:Neprilysin